R.L. Jones

Travelling and embedded policy: the case of knowledge transfer

Knowledge transfer (KT) has entered the higher education arena in the UK as the ‘third sector’ of higher education activity—along with research and teaching. Its antecedents lie in the commercialization and technology transfer of the late 1980s and 1990s, and this business‐like orientation remains dominant in the KT policy discourse. This paper explores the extent to which policy for KT may be understood both as ‘travelling’ policy shaped by globalizing trends in pursuit of successful competition in the new knowledge economy (KE) and as ‘embedded’ policy mediated by local contextual factors that may translate policy to reflect local priorities and meanings. In considering evidence of ‘embedded’ policy the paper develops its arguments through preliminary analysis of KT policy in Scotland where—at least at the level of discourse—there is an attempt in post‐devolution Scotland to encourage KT in the broader public interest. However, KT’s antecedents may continue to shape the engagement of academic staff in Scotland, as may the wider context of UK policy steering in higher education.

Prostaglandin E receptor subtypes in smooth muscle: agonist activities of stable prostacyclin analogues

1 The agonist activities of a range of prostaglandin analogues on smooth muscle preparations sensitive to prostaglandin E2 (PGE2) have been investigated. When necessary thromboxane‐like activity was eliminated using the thromboxane receptor antagonists EP 045 and EP 092. 2 On the bullock iris sphincter, rat stomach fundus and guinea‐pig trachea, (±) ω‐tetranor‐16‐p‐chlorophenoxy PGE2 (ICI 80205) and 16,16‐dimethyl PGE2 were more active contractile agents than PGE2, whereas for relaxant activity on the cat trachea, guinea‐pig trachea and dog hind limb arterial vessels in vivo the order of potency was reversed. 11‐Deoxy PGE, exhibited greater relaxant than contractile activity when compared to PGE2. 3 Iloprost and 6a‐carba‐Δ6,6aPGI1 (potent mimetics of PGI2) showed high contractile activity on the PGE‐sensitive preparations. PGI2 was less active and another potent PGI2 mimetic, ZK 96480, showed only very weak activity. When tested, the dibenzoxazepines SC 19220 and SC 25191 blocked the contractile actions of iloprost and 6a‐carba‐Δ6,6aPGI1 and those of PGE2 and 16,16‐dimethyl PGE2 to similar extents. Each of the PGI2 analogues showed weak activity on the relaxant systems. 4 On the proximal portion of the ascending colon of the rat, PGI2, iloprost, 6a‐carba‐Δ6,6aPGI1 and ZK 96480 always inhibited spontaneous activity at nanomolar concentrations. PGE2 and PGE1 showed weak contractile activity. The distal portion of the ascending colon was more responsive to the contractile action of PGE analogues: both iloprost and 6a‐carba‐Δ6,6aPGI1 showed evidence of contractile activity, whereas PGI2 and ZK 96480 always inhibited spontaneous activity. 5 Evidence was obtained that the rat stomach fundus also contains a PGF receptor; (±) ω‐tetranor‐16‐m‐trifluoromethylphenoxy PGF2α (ICI 81008) acted as a specific agonist. PGF2α and its ω‐tetranor‐16‐p‐fluorophenoxy analogue produced a higher maximum response that ICI 81008 probably due to their additional agonist action at the PGE receptor. 6 The data support the hypothesis that there are two subtypes of the PGE receptor. ZK 96480 has minimal activity on both receptor subtypes and appears to be a highly specific PGI2 mimetic.

Characterization of receptors involved in the direct and indirect actions of prostaglandins E and I on the guinea-pig ileum

1 . A study of the effects of prostaglandin E2 (PGE2) and eleven synthetic analogues on the guinea‐pig isolated ileum preparation has revealed three distinct contractile actions, each associated with a different prostaglandin E (EP‐) receptor subtype. In addition, PGI2 (prostacyclin) and its stable analogues can activate prostaglandin I (IP‐) receptors to elicit both contraction and relaxation of the ileum. 2 . Two of the PGE actions involve direct stimulation of the smooth muscle, being unaffected by 1 μm morphine treatment. One action is blocked by AH 6809 at micromolar concentrations and ICI 80205 and 16,16‐dimethyl PGE2 are particularly potent agonists. Activation of EP1‐receptors appears to be involved. The second action is unaffected by AH 6809; sulprostone and MB 28767 are potent agonists. Comparison with agonist potency rankings on the guinea‐pig vas deferens indicates that EP3‐receptors may be involved. 3 . The third PGE effect and the stimulant PGI effect are blocked by morphine, indicating enteric neurones and/or sensory nerve terminals as sites of action. EP2‐receptors may be involved in the PGE action, in view of the marked effect of morphine on the contractile actions of misoprostol, 11‐deoxy PGE2‐1‐alcohol, 11‐deoxy PGE1 and butaprost, all of which show some selectivity for EP2‐receptors. The PGI action is most easily studied with cicaprost (EC25 = 1.3 nm), since iloprost, carbacyclin and to a lesser extent PGI2 also have agonist activity at EP1‐receptors. 4 . The contractile action of 17‐phenyl‐ω‐trinor PGE2 on the ileum is unaffected by morphine. Since this analogue shows only weak agonist activity on the rabbit jugular vein (EP2 preparation) and guinea‐pig vas deferens (EP3), it may be a more useful standard agonist than PGE2 in EP1‐receptor studies. 5 . In the presence of morphine and AH 6809, cicaprost inhibits histamine‐induced contractions (IC25 = 22 nm). PGI2 and iloprost show mixed inhibitory/potentiating actions, whereas carbacyclin only potentiates histamine contractions. This IP‐receptor‐mediated inhibition may account for the bell‐shaped log concentration‐response curve of cicaprost (no inhibitors present) and the very marked block of iloprost‐induced contractions by AH 6809. 6 . We have found no evidence for either IP‐receptors mediating direct contraction or EP‐receptors mediating inhibition of the ileum longitudinal smooth muscle, as has been suggested in the literature. 7 . In view of the complexity of prostanoid action on the guinea‐pig ileum we feel that the preparation must be used with caution to ascertain the EP1 agonist or antagonist potencies of novel compounds.

Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

1 The preparation of enantiomerically pure [3H]‐15 (S) 9, 11‐epoxymethano PGH2 (a thromboxane A2‐like agonist) has enabled the binding of ligands to the thromboxane receptor of the human platelet to be studied. 2 The binding of the radio‐ligand to washed human platelets has 3 components. One component is not displaceable by ‘cold’ 9, 11‐epoxymethano PGH2 and its concentration‐binding plot is roughly linear. The other 2 components are displaceable and saturable, and the larger of the two, which is sensitive to the stereochemistry of the C15 secondary alcohol, appears to represent the thromboxane receptor. About 1700 15(S)9, 11‐epoxymethano PGH2 molecules are specifically bound to a single platelet and 50% of this binding is achieved with a concentration of 75 nM. 3 Displacement of [3H]‐15(S)9, 11‐epoxymethano PGH2 is effected by (a) TXA2 and PGH2 and a number of bicyclic stable analogues (e.g. 9,11‐azo PGH2), all of which produce irreversible aggregation of human platelets; (b) analogues of PGF2α with potent thromboxane‐like activity (e.g. ICI 79939); (c) compounds with partial agonist activity on the platelet thromboxane system (e.g. CTA2); (d) Thromboxane/endoperoxide analogues which specifically antagonize thromboxane‐like actions on the human platelet (e.g. PTA2 and EP 045). 4 Displacement is not achieved with the natural prostaglandins PGE2, PGD2 and PGF2α. Neither the thromboxane‐synthetase inhibitor dazoxiben nor R(+)‐trimethoquinol have high displacing activity. 5 The correlation of radio‐ligand displacement with the biological activity of the competing ligands is discussed in relation to the nature of the thromboxane receptor on the human platelet.

The 2003 UK Government Higher Education White Paper: a critical assessment of its implications for the access and widening participation agenda

Fair access and widening participation currently occupy a prominent position in the UK higher education agenda, but these terms remain ambiguous. In this paper we identify two prominent strands of policy in the governments approach to access and the widening of participation and contrast these with a third, more progressive perspective. The academic strand seeks to attract ‘gifted and talented’ young people into an unreformed higher education system. The second strand, which we term the utilitarian approach, posits a need for reform. However, this is undertaken largely to meet the requirements of employers and the economy. In contrast, a transformative approach values diversity and focuses on creating a system of higher education that does not place the burden of change upon potential entrants. This framework is used to explore some of the implications of the governments White Paper The future of higher education. First, the purpose of higher education is discussed, with particular reference to the distinction between economic and social objectives. Second, the governments view of the structure of the higher education sector is examined, by scrutinizing the notion of institutional differentiation and the role of the access regulator. We conclude that within a more differentiated higher education sector different aspects of the access discourse will become dominant in different types of institutions.

The identification of trihydroxyeicosatrienoic acids as products from the incubation of arachidonic acid with washed blood platelets

Arachidonic acid is converted by washed platelets from man, horse and dog into a mixture of 8,9,12-trihydroxyeicosa-5,10,14-trienoic acid and 8,11,12-trihydroxyeicosa-5,9,14-trienoic acid (termed 8,9,12-THETA and 8,11,12-THETA respectively and THETA collectively). Gas chromatographic--mass spectrometric evidence of structure is discussed.

Investigation of the prostaglandin E (EP-) receptor subtype mediating relaxation of the rabbit jugular vein

1 Prostaglandin E2 (PGE2) relaxes circular smooth muscle of the rabbit isolated jugular vein at very low concentrations (mean pIC50 against histamine‐induced contraction = 9.34). This effect is not blocked by the EP1‐receptor antagonist, AH 6809 (2 μm). 2 From a group of prostaglandin E analogues examined, 16,16‐dimethyl PGE2, misoprostol, 11‐deoxy PGE2‐1‐alcohol and 11‐deoxy PGE1 were highly potent relaxant agents, whereas 17‐phenyl‐ω‐trinor PGE2, MB 28767 and butaprost had low potency and sulprostone and oxoprostol were virtually inactive. 3 Comparison of the jugular vein data with published data for inhibitory agonist potencies on the cat trachea (EP2 preparation) and the field‐stimulated guinea‐pig vas deferens (EP3) indicates that the EP‐receptor in the rabbit jugular vein is closest to the EP2 subtype. However, the correlation is not entirely convincing. For example, butaprost, 16,16‐dimethyl PGE2 and 11‐deoxy PGE1 are of similar potency on the cat trachea, whereas butaprost is about 300 times less potent than the other two analogues on the jugular vein. The existence of more than one EP2‐receptor appears possible. 4 It was felt that the activity of butaprost required further investigation in view of the claim that it is a specific EP2‐receptor agonist. We have shown that butaprost has very low inhibitory activity on the guinea‐pig vas deferens, a very sensitive EP3‐receptor containing preparation. However, on the chick ileum, the original EP3 preparation, butaprost showed potent contractile activity (pEC25 ˜ 8.0). In addition, its maximum response was lower than that of PGE2; lower maxima were also found for sulprostone, MB 28767 and oxoprostol, but not for ICI 80205, 16,16‐dimethyl PGE2 and 17‐phenyl‐ω‐trinor PGE2. The maximal response to a combination of either sulprostone and butaprost or sulprostone and PGE2 was similar to that achieved by PGE2 alone. Analysis of the interaction between sulprostone and PGE2 appears to exclude a partial agonist action for sulprostone. Furthermore neither sulprostone nor butaprost appear to have inhibitory activity on the ileum. AH 6809 at 2 μm produced only a small shift of the PGE2 log concentration‐response curve. 5 It is likely that contraction of the longitudinal smooth muscle of the chick ileum is mediated by (at least) two EP‐receptor subtypes; activation of only one receptor system does not induce the maximum response (i.e. the acetylcholine maximum) of the preparation. One receptor could be an EP3 subtype, at which sulprostone exerts a selective agonist action. The other receptor is unlikely to be an EP1 subtype, because of the high agonist potency of butaprost, the low agonist potency of iloprost, and the low antagonist potency of AH 6809. An alternative hypothesis is that the chick ileum contains a novel EP‐receptor subtype in addition to an EP3‐receptor.

Functional and ligand binding studies suggest heterogeneity of platelet prostacyclin receptors.

1 This study describes attempts to compare prostacyclin (IP‐) receptors in human, pig, horse, rabbit and rat platelets and in circular muscle of human, rabbit and dog mesenteric and pig gastroepiploic arteries. Three stable prostacyclin analogues, iloprost, cicaprost and 6a‐carba‐prostacyclin (6a‐carba‐PGI2) and a prostaglandin endoperoxide analogue EP 157 (previously shown to mimic prostacyclin on human platelets) were used. 2 Our main conclusion is that prostacyclin receptors on human, pig and horse platelets are similar in nature, but distinct from those on rabbit and rat platelets. Functional studies (inhibition of aggregation) showed that iloprost and cicaprost always had similar potencies whereas 6a‐carba PGI2 was much more potent than EP 157 on rabbit and rat platelets (300 and 1000 fold on a molar basis) compared with human, pig and horse platelets (2, 7 and 7 fold respectively). Measurement of initial rates of cyclic AMP production confirmed these orders of potency. 3 Although pig platelets were quite sensitive to inhibition by EP 157 (threshold = 10 nM in some experiments), maximal inhibition of aggregation was not always achieved (20 μm). EP 157 also produced only small elevations of cyclic AMP and inhibited rises in cyclic AMP induced by iloprost. It is possible that EP 157 has a lower efficacy than iloprost at the IP‐receptor and on pig platelets it can sometimes act as a partial agonist. 4 Human, pig and horse platelet membranes bound [3H]‐iloprost at 30°C and this binding was inhibited by the four prostanoids. On human and pig membranes the order of potency was cicaprost = iloprost > 6a‐carba PGI2 > EP 157. The order of potency may be similar on horse platelet membranes, but the analysis is complicated by the presence of a second component of [3H]‐iloprost binding that is inhibited by iloprost and 6a‐carba PGI2 but not by cicaprost. This binding may be due to the presence of an EP1‐receptor, since iloprost and 6a‐carba PGI2 but not cicaprost are known to have potent EP1‐receptor agonist actions on smooth muscle preparations. IC50 values for cicaprost inhibition on human, pig and horse membranes were 110, 90 and 165 nM respectively. The need for IP‐receptor radioligands of greater specificity is apparent from these studies. 5 Minimal binding of [3H]‐iloprost to rabbit and rat platelet membranes was obtained at 30°C. Lowering the incubation temperature to 4°C and ensuring that the temperature did not rise during the filtration process increased binding and allowed inhibition curves to be obtained. The results suggest a lower binding affinity for [3H]‐iloprost, associated with a higher dissociation rate for the radioligand‐receptor complex. IC50 values for cicaprost were 900 nM for rabbit and 640 nM for rat platelets. In a similar manner to horse platelet membranes, the presence of a second binding site for [3H]‐iloprost was detected on rabbit platelet membranes. 6 Sensitivity to the relaxant action of iloprost on the arterial smooth muscle preparations decreased in the order: human mesenteric, dog mesenteric, rabbit mesenteric, pig gastro‐epiploic. Cicaprost was always slightly more potent than iloprost (1.2–2.8 fold). On the pig vessel preparation 6a‐carba PGI2 did not produce complete relaxation. The possibility that this is due to an opposing contractile action mediated via EP1 or EP3 receptors is discussed. 7 EP 157 relaxed the human, pig and rabbit arterial preparations at concentrations 100–200 times those of iloprost. This correlates well with its IP‐receptor agonist potency on human, pig and horse platelets. The results obtained with EP 157 further demonstrate the potential difficulties in separating platelet inhibitory and vasodilator properties of prostacyclin mimetics in man.

Heterogeneity of thromboxane A2 (TP‐) receptors: evidence from antagonist but not agonist potency measurements

1 Thromboxane A2 (TP‐) receptors in human, rat and rabbit platelets and in smooth muscle of guinea‐pig trachea, rat aorta and rabbit aorta have been characterized by measurement of the potencies of agonists and antagonists having considerable variations in chemical structure. 2 On each washed platelet system, eight prostanoids induced maximal irreversible aggregation (full agonists) and the potency ranking was EP 171 > STA2 > 9,11‐azo PGH2 > 9,11‐endoxy‐10a‐homo PGH2 > U‐46619 (standard) > PGH2 = 16‐p‐fluorophenoxy‐ω‐tetranor PGF2α > 16,16‐dimethyl PGF2α. Correlations between the three platelet preparations for both absolute and relative potencies were good. On human platelets, STA2, at concentrations above that required for maximum aggregation, exerted an inhibitory effect which was independent of its interaction with the TP‐receptor. 3 Five prostanoids, EP 109, EP 167, EP 204, PTA2 and 16,20‐methano PTA2, exhibited partial agonist activity on the platelet and smooth muscle preparations. There was good agreement between absolute potencies on the six preparations; on platelets potency was assessed from shape change measurements, since aggregation, when present, always showed a very shallow concentration‐response relationship. The magnitude of the maximum response induced by each compound decreased in the order listed above, to the extent that 16,20‐methano PTA2 could be treated as a pure antagonist. 4 With U‐46619 as agonist, the pA2 values of seven antagonists were found to be very similar on human and rat platelets. The potency ranking was EP 169 > AH 23848 > EP 092 > ONO 11120 > EP 115 = 16,20‐methano PTA2 > BM 13177. There was a similar trend on rabbit platelets but pA2 values were 1.0–1.5 log units smaller; the exception was BM 13177 which had similar affinities. The antagonism produced by EP 169 and AH 23848 was surmountable on rabbit platelets but not on human and rat platelets. 5 None of the antagonists was highly potent on the rabbit aorta (pA2 values < 7.5 by Schild analysis). Affinities on the guinea‐pig trachea and the rat aorta were higher and in the same range as those obtained for human and rat platelets. However the correlations of pA2 values between any pair of smooth muscle preparations and between any pair of platelet/smooth muscle preparations were either weak or not significant (P > 0.05). 6 The excellent agreement for both full and partial agonist potencies between the six preparations provides no evidence for TP‐receptor subtypes and further suggests that the agonist recognition sites of the TP‐receptors could be very similar, if not identical, in nature. In contrast, the different antagonist affinities found in this and other published studies indicate heterogeneity of TP‐receptors. However, classification into TP1‐, TP2‐receptors, etc. on the basis of the limited antagonist data available does not appear appropriate at this time.

The identification of an epoxy-hydroxy acid as a product from the incubation of arachidonic acid with washed blood platelets.

An epoxy-hydroxy compound, 10-hydroxy-11,12-epoxy-eicosa-5,8,14-trienoic acid, has been identified as a product on incubation of arachidonic acid with washed blood platelets from human, horse, cat, dog and rabbit. Gas chromatographic - mass spectrometric (GC-MS) evidence of structure is discussed.